1. Field Of The Invention
The present invention relates to a novel combination comprising dextromethorphan in combination with a suitable anti-epileptic drug. More specifically the invention is directed to a pharmaceutical combination and method of treating epilepsy and other convulsions by introducing to the patient an effective amount of a composition comprised of dextromethorphan or one of the similarly related compounds as a potentiating agent in combination with at least one known anti-epileptic drug which does not either inhibit or enhance binding at the [.sup.3 H]dextromethorphan receptor site in the central nervous system, but does act either to inhibit excitatory amino acid neutrotransmission or to otherwise reduce neutronal excitability.
2. Description Of The Prior Art
In recent years the field of medicine has had varying success in treating epileptic seizures. Most types of seizures, including induced generalized or focal seizures, can be treated with one of several anti-epileptic hydantoins and in particular diphenylhydantoin (DPH) commonly referred to as phenytoin or dilantin. Dilantin is the registered trademark of the Parke-Davis Company.
Dilantin has the advantage of usually inhibiting epileptic activity without causing a general depression of the central nervous system. Moreover, dilantin can limit the development of maximal seizure activity and reduce the spread of the seizure process from an active focus. Because of these desirable characteristics dilantin has been successfully used for many years as an anticonvulsant in the treatment of epilepsy.
The use of dilantin, as well as many other anticonvulsant agents, has been somewhat limited, however, since most effective anticonvulsants possess the distinct disadvantage of being toxic at some concentrations. Although the effectiveness of dilantin in treating seizures increases with dosage, the adverse toxic effects also increase to an unacceptable and often times dangerous level. Many of these adverse toxic effects further increase with the length of exposure and vary with the mode of administration of the anticonvulsant thereby further limiting their use and necessitating the careful monitoring of the patient and constantly altering the medication and procedures.
The dose-dependent toxic effects associated with the continued use of dilantin, as well as other anticonvulsant hydantoins, include cerebellar vestibular effects (nystagmus, ataxia and diplopia vertigo) and central nervous system disturbances such as blurred vision, mydriasis and hyperactive tendon reflexes. Behavioral changed that have been associated with the use of dilantin include hyperactivity, confusion, dullness, drowsiness and hallucination. Further adverse toxic effects include increased frequency of seizures, peripheral neuropathy, gastrointestinal distress, gingival hyperplasia, osteomalacia, megaloblastic anemia, hirsutism, endocrine effects and lymphadenopathy. At very high doses, especially when administered intravenously, dilantin can cause cardiovascular collapse and depression of the central nervous system.
Accordingly, efforts have been made to develop an anti-epileptic drug or anticonvulsant agent having as few side effects as possible while maintaining efficacy. One such effort has been reported in Brain Res., 383:314-318, 1986 by Tortella.
Tortella, aided by earlier work, discovered that their antitussant, dextromethorphan, could serve as an effective anticonvulsant possessing an activity similar to that of dilantin. Dextromethorphan is a potent antitussive agent which has been used for many years in the medical field with few side effects. Most often, dextromethorphan is one of the active ingredients in over-the-counter cough and cold medications. Dextromethorphan is the non-narcotic stereoisomer (enantiomer) of the opioid L-3-methoxy-17-methylmorphinan.
Dextromethorphan when introduced by itself to laboratory test animals at a dose of 30 mg/kg has been shown to provide protection against transauricular maximal electroshock seizure (MES). Dextromethorphan has further been shown to have a somewhat longer protection time against MES than that exhibited by dilantin under standard testing conditions. In addition, Tortella demonstrated that the anticonvulsant potency of dilantin was enhanced (ED.sub.50 decreased) by co-administration of dextromethorphan in vivo. The use of dextromethorphan as a potentiating agent by Tortella was further extended to include, as potentiating compounds, compounds related to dextromethorphan or other antitussants which inhibit binding of [.sup.3 H]dextromethorphan to the central nervous system site with high affinity (IC.sub.50 &lt;75 nM).
The discovery by Tortella was based, at least in part, by earlier findings reported by Craviso and Musacchio in Mol. Pharmacol. 23:619-628 and 23:629-640 (1983). These experiments were in part carried out to determine whether antitussants such as dextromethorhan bind at a subset of opiate receptors. Craviso and Musacchio demonstrated high affinity binding of [.sup.3 H]dextromethorphan to homogenates of guinea pig, rat and mouse lower brainstem (Kd&lt;20 nM). Of significant importance is that the opiate antagonists and agonists did not compete effectively at the same site as dextromethorphan. However, it was shown that some antitussants including carbetapentane, caramiphen and dimethoxanate inhibited binding with IC.sub.50 's in the 1 to 75 nM range.
Craviso and Mussacchio's report further revealed that the binding of [.sup.3 H]dextromethorphan was effectively inhibited in vitro by a member of other compounds such as selective antidepressants, phenothiazines, neuroleptics, antihistamines and muscarinic agents and calcium channel blockers (IC.sub.50 &lt;100 nM). However, the primary importance of their work was in the discovery that the in vitro binding of [.sup.3 H]dextromethorphan to the central nervous system sites was markedly increased in the presence of certain compounds including noscapine and the anticonvulsant, dilantin. It was noted, however, that the anti-convulsant carbamazepine did not inhibit or enhance [.sup.3 H]dextromethorphan binding. Additionally, the research fell short, since they were unable to predict which compounds would modify (inhibit or enhance) [.sup.3 H]dextromethorphan binding at concentrations considered reasonably by those skilled in the art, and which would not. The discovery of Tortella and Musacchio of the anticonvulsant potentiating characteristics of dextromethorphan was, thus, based on the binding site of [.sup.3 H]dextromethorphan and the binding of compounds, including anticonvulsants, at that site. The discovery of Tortella and Musacchio was, however, rather narrow since the number of suitable potentiating compounds was, thus, limited by the requirements that the potentiators are compounds that inhibit or enhance dextromethorphan binding or otherwise bind to the dextromethorphan site at nM concentrations.
It has been known that dextromethorphan is rapidly metabolized (demethylated) in vivo to yield dextrorohan (DEX) and two lesser metabolites, (+) D-(3)methoxy-morphinan and (+) D-hydroxymorphinan respectively. In rats, dogs and humans the ratio of dextrorphan to dextromethorphan in plasma and urine typically exceeds 100 to 1. The absolute plasma levels of dextromethorphan following 20 to 60 mg p.o. in humans rarely exceeds five nanograms per milliliters whereas the dextrorphan levels are 380 nanograms per milliliter. In man, dextrorphan represents the major metabolite, since the other demethylation products in urine, after eight hours, account for less than 15% of the dose administered. More importantly, the major metabolite, dextrorphan, has a relatively low affinity (2500 nM) for the [.sup.3 H]dextromethorphan receptor but a relatively high affinity for the [.sup.3 H]TCP-labeled-NMDA-linked receptor (&lt;10 nM).
Since dextromethorphan is rapidly converted to dextrorphan in vivo, these data raise the possibility that dextromethorphan's anticonvulsant effects may not be directly related to the [.sup.3 H]dextromethorphan binding site as suggested by Tortella and Musacchio, but may result from the action of metabolites at other (e.g., PCP/NMDA, calcium channels) receptors.
The discovery by Tortella and Musacchio was also severely restricted to the belief that dextromethorphan and the related non-opiate compounds were able to potentiate only anti-epileptic anticonvulsants that enhanced [.sup.3 H]dextromethorphan binding in the central nervous system. Many commonly used anticonvulsants do not complete, enhance or otherwise interact with dextromethorphan at the [.sup.3 H]dextromethorphan-labeled binding site at nM concentrations. Of particular importance of the excluded anticonvulsants are compounds such as carbamazepine and excitatory amino acid antagonists and including ketamine, dexoxadrol and pencyclidine. Contrary to the teachings of the prior art, the present discovery indicates that dextromethorphan is effective at potentiating anticonvulsant activity of compounds that do not inhibit or enhance dextromethorphan binding to brain. In addition, the present invention relates to a composition of matter and a method of treating epilepsy using dextromethorphan or its related compounds as a potentiating agent for anticonvulsants such as carbamazepine.